The potential use of smallpox as a bioterrorism agent has created a need to fully understand the pathogenesis of this virus and related Poxviridae family members. Poxviruses have evolved multiple mechanisms to modulate and evade the host immune response, compromising viral recognition and clearance as well as diminishing long-lasting protective immunity. Using vaccinia virus (VV) as a model of poxvirus infection, the goal of this Program Project is to understand how poxviruses alter the function of antigen presenting cells (APCs). The main hypothesis is that poxvirus modulation of antigen presenting cell function prevents the development of an effective adaptive immune response and enhances viral pathogenesis. To achieve our goal, this application combines four projects from a group of highly interactive investigators with complementary approaches. These projects will assess how the poxvirus phosphatase VH1 alters signaling pathways in antigen presenting cells, investigate how VV inhibits DC maturation which prevents the integration of the innate and adaptive immune responses, and study the biochemical and cellular properties that are altered by VV to escape from the presentation by CD1, and MHC class I and class II molecules. These four research projects will be supported by an administrative and resource core to help the investigators further define the pathogenesis of poxvirus infection, which will lead to improved strategies for vaccine development and disease treatment.